Genetic, pathological, modeling and human biomarker studies all demonstrate that alterations in the tau protein are tightly linked to neurodegeneration in diverse tauopathies including, but not limited to, Alzheimer?s disease (AD) and fronto-temporal dementia (FTD). Tau-inclusion pathology, generically referred to as tauopathy, correlates with cognitive decline and neuronal loss in primary tauopathies and AD. In model systems, expression of FTD-linked tau mutations can lead to tau inclusion pathology, cellular dysfunction and neurodegeneration. As the tauopathy arises, post-translational modifications of tau appear, but in many instances, it is unclear if these modifications are markers of dysfunction or drivers of pathology. Prion-like conformational templating occurs in model systems and has been postulated, but not proven, to explain spread of pathology and different clinical syndromes associated with tauopathy. Yet, despite intensive study, the field has developed a limited portfolio of tau-targeting therapies, and many aspects of tau-induced neurodegeneration remain poorly understood. We have recently developed an ex vivo recombinant adeno-associated virus (rAAV) based organotypic brain slice culture (BSC) model of tauopathy that develops widespread mature tau inclusions recapitulating those in human tauopathies by 1 month in culture. We have i) shown by multiple biochemical and histological means that these are mature tau inclusions, ii) observed a relationship between cell death and tauopathy formation, iii) demonstrated the utility of this model for evaluating therapeutic strategies designed to alter tauopathy, iv) demonstrated that effects observed in the BSC studies are predictive of effects in vivo. We now propose three aims that leverage the BSC tauopathy model to increase understanding of the role tau plays in causing cellular dysfunction and to guide future therapeutic discovery: Aim 1. Further characterize and extend the rAAV-based BSC tauopathy model to gain additional insight into mechanisms that regulate tauopathy and tau-induced cellular degeneration. Aim 2. Evaluate known and emerging therapeutic targets and strategies designed to alter the tauopathy itself or tau induced cellular degeneration. Aim 3. Probe mechanisms by which tau induces cellular dysfunction.